Abstract
In various systemic cancers, interleukin 12 (IL-12) induces anti-tumour immunity mediated by T lymphocytes and natural killer cells. To determine whether IL-12 has anti-tumour activity against malignant gliomas in the central nervous system (CNS), which is considered to be an immunologically privileged site, we treated mice with meningeal gliomatosis by intraperitoneal (i.p.) or intrathecal (i.t.) administration of recombinant murine IL-12. Although untreated mice revealed symptoms, such as body weight loss or paraplegia as a result of the meningeal gliomatosis within 8 days after tumour inoculation, 80% of the mice treated with IL-12 at 0.5 microg i.p. were cured. Many lymphocytes, mostly CD4+ and CD8+ cells, infiltrated to the tumours of IL-12-treated mice. The numbers of these cells increased in the cervical lymph nodes, into which the cerebrospinal fluid drains, and there they secreted a considerable amount of interferon-gamma. Mice cured by IL-12 rejected subcutaneous or i.t. rechallenge with their original glioma cells, but the same mice were not able to reject other syngeneic tumour cells. These results indicate that the immune system recognizes malignant glioma cells in the subarachnoid space of the CNS and that systemic IL-12 may produce effective anti-tumour activity and long-lasting tumour-specific immunity.
Highlights
We demonstrated that systemically administered interleukin 12 (IL-12) produces a potent anti-tumour effect and long-lasting immunity in the central nervous system (CNS) by promoting the proliferation of tumour-infiltrating lymphocyte (TIL) and by stimulating local IFN-y production
Results showed that the local administration of IL-12 into the CNS was less effective in vivo than the systemic administration
natural killer (NK) cells alone, without T cells, may not be capable of rejecting tumour cells transplanted into the CNS
Summary
RSV-M mouse glioma cells (Kumanishi et al, 1973) and C3H/MCA clone 15 fibrosarcoma cells (Rapp et al, 1975) derived from C3H/HeN mice were maintained in Dulbecco's modified Eagle medium (DMEM) with 10% heat-inactivated fetal bovine serum (FBS) in a humidified 10% carbon dioxide-in-air atmosphere at 37°C. An MG model was produced in 7-week-old female C3H/HeN mice weighing 18-21 g by inoculating 50 gl of the cell suspension into the cistema magna using a 26-gauge needle. An MG model was produced in 7-week-old female BALB/c-nu/nu mice by inoculating 5 x 106 cells as described above. (0.5 gg 200 ,ul-') into the BALB/c-nu/nu mice once daily from days 3 to 7 after tumour inoculation. Animals were handled in accordance with the guidelines of the Animal Committee of Osaka University Medical School and UKCCR guidelines for the welfare of animals in experimental neoplasia (UKCCR, 1988)
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